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Emil von Behring - Nobel Lecture

Nobel Lecture, December 12, 1901

Serum Therapy in Therapeutics and Medical Science

Serum therapy in the form in which it finds
application in the treatment of diphtheria patients is an
antitoxic or detoxicating curative method. It is based on the
view, held by Löffler in Germany and by Roux in France, that
the parasites causing diphtheria, the Löffler diphtheria
bacilli, do not themselves cause diphtheria, but that they
produce poisons which cause the disease to develop. Without this
preliminary work by Löffler and Roux there would be no serum
treatment for diphtheria.

When the diphtheria poison is rendered
harmless within the human organism, then the diphtheria bacilli
behave like the innumerable micro-organisms which we absorb
without suffering harm every day and like those micro-organisms
which correspond morphologically with the diphtheria bacilli,
but, from the outset, have no capacity to produce poisons
(pseudo-diphtheria bacilli). The poison excreted by the bacilli
is the diphtheria bacilli's dangerous weapon against the human
being, without which weapon they would be delivered over
helplessly to the natural prophylactic power of the living human
organism.

The way in which the diphtheria bacilli,
after penetrating into the human body, release then poison and
how this poison develops its destructive activity has been the
subject of many interesting investigations, the result of which
can be summed up briefly as follows: In a typical clinical
picture of diphtheria in human beings, as summarized for the
first time 80 years ago by the Frenchman Bretonneau, the
diphtheria bacilli are first localized in the pharyngeal
amygdala, which, in all probability, they reach principally via
the breath, but also in substances which we take in by way of
nourishment. In the niches and small cavities of the amygdala the
diphtheria bacilli can multiply as though in an artificial
incubator and excrete their poisons. In animals, the organ,
called "amygdala" tonsils) on account of its shape (L. "amygdala"
= almond), is missing and this is probably the reason why
epidemics of diphtheria are the tragic privilege of human beings.
The diphtheria poison gets into the blood stream by way of the
lymphatic vessels and starts up inflammatory processes from there
in the various organs. The inflammatory symptoms are outwardly
visible chiefly in the proximity of the site of production, on
the pharyngeal mucous membrane and in the larynx.

If we now introduce the diphtheria serum as
an antitoxin into the blood by injecting it under the skin, this
antitoxin will reach all parts of the body to which the blood has
access. If the injection takes place at a time when the
diphtheria bacilli have not yet begun their destructive activity,
then the secondary inflammatory phenomena of diphtheria toxicity
will not arise. We speak then of immunization or of preventative
or prophylactic serum therapy. If, on the other hand, the toxic
process has already begun, then the already existing inflammatory
processes will follow their natural course, for the anti-toxin
exerts no influence, either useful or harmful, on the
substrata of the inflammation, on the cells and organs. In
this case, all that can influence the already existing disease is
firstly to render harmless the poison which has already
reached the body fluids, and secondly to prevent the entry
of fresh supplies of active poison into the blood stream. It is
easily understandable that the diphtheria serum has an
abortive action, but it is not the disease which is
cut off but the creation of new disease-engendering
substances.

It will be seen from this how important
early use of diphtheria serum is. The longer one delays
the injection after the start of the illness, the more existing
focal points of inflammation and the more disturbances of vital
functions will threaten health and life.

In addition, a certain time must elapse
from the injection of the serum until its antitoxic and healing
activity in the affected parts of the body can develop. Also,
serum injected under the skin does not pass straight into the
blood vessels but first into the lymphatic vessels. From here it
takes several hours before passing gradually into the blood
stream and further time still is needed before it is diffused,
not only everywhere in the blood stream, but also into the
extra-vascular poison-containing fluids. This interval between
injection and detoxification can mean the difference between life
and death for the threatened individual and I have asked myself
whether, in the interest of the patient, this interval could not
be shortened. It can indeed be done if the serum is injected
directly into the blood stream instead of under the skin.
According to experimental investigations carried out by my
erstwhile collaborators, Dr. Knorr and Dr. Ransom, about 8 hours
can be saved in this way. Furthermore, it is possible to have a
local effect on the poison-producing localities by using dilute
serum solution as a mouth wash to rinse the poisoned pharyngeal
organs. So that we may recognize the position which serum
therapeutics have gained in the treatment of diseases, as
compared with other methods in medicine, I hope you will allow me
to use one or two technical terms, not only because these have,
during the course of time, come to embody a well-known and
generally respected concept, but also because these technical
expressions, taken from Latin and Greek, are more suited to
international understanding than more modern expressions which we
might use in their place.

Since earliest times, in that sphere of
medicine which is responsible for the analysis of the symptoms of
disease, their cause and natural or artificially induced
conquest, namely pathology, humoral and solidistic pathologists
have been in opposition to one another. In the last century the
solidistic pathologists won the upper hand and the form which
Virchow has given to the solidistic pathology by the foundation
of cellular pathology is now so firmly established that
the old humoral pathology can probably be regarded as having been
finally laid to rest. With the victory of solidistic
pathology, however, there has now arrived, pari passu, in
the teaching hospitals a solidistic and cellular therapy
of which one cannot speak so highly as in the case of the
cellular pathology.

In the treatment of wounds, solidistic
trend in therapy expressed itself more in salves, balsams,
alteratives, which were supposed to influence the diseased body
elements in ill-looking wounds to new and different activity. As
you know, this aspect of solidistic therapy has vanished from
medicine since Lister, with epoch-making success, laid down the
principle, which he taught us to follow down to the smallest
detail: "Keep fingers away from wounds, leave the cells as much
as possible undisturbed, but take care that noxious agents from
outside are kept away from wounds and cells".

In internal medicine, however, solidistic
therapy remained "faute de mieux". New remedies were constantly
coming on to the market and into use in practice which were
supposed to curb, with anti-febrins, the vigorous activity of the
cells aroused by fever, encourage the will to live and alter the
misdirected cell activity. I do not need to quote instances when
I maintain that we were all reared in the solidistic- and
cellular-therapy dogma according to which the morbid
manifestations of life are and must remain the subject of
internal therapy. A glance at any Government-sanctioned
Pharmacopoeia will show that even now medicaments are classified
against a background of this viewpoint.

The detoxicating, or as it is also called,
the antitoxic serum therapy, is, on the other hand,
humoral therapy. Just as little as it has any direct
influence on the diphtheria bacilli, is it able to have any
direct action, whatever, on the living body elements of the
patient who either has, or is threatened with, diphtheria. The
detoxicating process acts exclusively in the body fluids,
in the blood, in the lymphs and in the pericellular lymphatic
areas. I must emphasize this especially, because many authors
take the view that the diphtheria anti-toxin can also neutralize
the poison which has penetrated into the body cells and become
established there. My own experience runs entirely contrary to
such a view.

Serum therapy in the treatment of
diphtheria is, therefore, humoral therapy in the strictest sense
of the word. It leads us back to the supposedly long-abandoned
crasis theory which attributed an important role in the
development and overcoming of disease to the peculiarities of the
mixing of the substances solved in the body fluids. As long as
there is active diphtheria poison in the body fluids, then a
dyscrasia exists. After inactivation of the diphtheria
poison, or in other words after the detoxication of the body
fluids by the addition of diphtheria antitoxin, the
dyscrasia is overcome; in its place appears, so to say, a
eucrasia. I do not object if someone tells me that the
process of disease does not consist in a faulty mixture of
fluids, but in the abnormal functioning of living body elements,
the solids of the whole organism. In this sense, there can, in
fact, only be solidistic pathology or cellular
pathology, and never humoral pathology since, indeed the
lifeless, inert body fluids cannot be attacked by any or illness. In
so far, however, as the diseased function of the living body
elements is, in the main, conditioned by the incorrect mixture of
body fluids, I find the linguistic inconsistency of the use of
the word humoral pathology no worse than if one speaks of
pathological anatomy, although the subject matter of this
discipline concerns cadaver anatomy and cannot really be
attributed to cadavers. However this may be, no one doubts any
more of the existence of a humoral therapy since antitoxic
diphtheria therapy has found an assured place for itself in
medicine.

I must add another important epithet to the
word serum therapy in order to characterize its position
in medicine. It is aetiological therapy in contrast to the
symptomatic therapy just described. As in the case of the Lister
treatment of localized wound infections, serum therapy also, in
the treatment of general infections, holds to the principle
"leave the cells in peace and simply take care that noxious
agents from outside are kept out, or, if they once get into the
body, are removed". The internal anti-infectious therapy would
appear to have the more difficult task, and as long as it was
thought that anti-infectious activity could only be carried out
by killing the living disease germs, the pessimists appeared to
be justified in making the discouraging statement that
"internal disinfection would always remain impossible". If
now an internal disinfection has, nevertheless, been achieved,
this is not thanks to speculation or change of doctrine, but
thanks to the fact that Nature herself has been taken as a guide.
I doubt whether it will ever be possible to establish
artificially the antitoxic principle of serum therapy in
diphtheria, without the aid of vital organization and secretion
faculties. It is one of the most wonderful things imaginable to
see how the supply of poison becomes the prerequisite for the
appearance of the antidote in the poisoned living organism, how
then the antidote in the blood reaches a state of almost
unbelievable antitoxic energy through the systematic increase of
the poison supply, how the bearers of this energy, the albumins
and globulins of the blood, show no sign of any chemical change
whatever, how the newly-won energy is so elective that we have no
other means of proving its existence than solely by the
diphtheria poison.

An attempt has been made to make a
comparison between the method of action of the antitoxic serum
albumin on the poison molecules with other compensating and
inactivating processes. In my first work, I myself used the
non-prejudicial expression "rendering the poison harmless",
replacing it later, following Ehrlich*, with the better sounding expression "poison
destroying". But I gave up this expression as well when I
realized that I was being credited, on account of it, with the
assumption that the poison molecule would be, to a certain
extent, demolished and so become non-poisonous. I began then to
speak of "neutralization", but right from the start I secured
myself against the opinion that the antitoxic and the toxic
protein combine in a way which resembles the formation of salts
from acid and alkali. Now I prefer to use the word "detoxication"
which makes no reference to the method of action. But if I want
to indicate roughly how I imagine this detoxicating process, then
I speak of "inactivation". I imagine, in fact, that, as regards
chemical analysis, the antitoxic and the toxic protein stay
exactly the same after detoxication as before; what
changes is simply the activated condition; in the same way as the
conductors of positive and negative electricity, before and after
compensation of their active conditions, remain the same
substances in terms of chemical analysis. Perhaps, at some later
date, work in the physico-chemical border territory which you
here see represented by such illustrious names as van't Hoff and
Arrhenius will
bring us to the point where we can refer to active protein
without the need of talking in parables!

With this example of antitoxic diphtheria
therapy, I have attempted to enumerate for you the chief
characteristics of serum therapy as a novum in therapeutics and
as a progressive step in medicine.

It is a humoral therapy, because its
activity develops only within the fluid and solved components of
the individual who is ill or threatened with illness. It has an
anti-infectious action brought about by internal disinfection,
but is, in this respect, in contrast to the anti-bacterial
disinfectant treatment methods which, for example, can be carried
out in laboratory experiments with the aid of the R. Pfeiffer's
bacteriolysin; because its activity is only detoxication, we call
it antitoxic. Because it does not influence the substrata of the
diseased manifestations, the cells and organs, but only the
cause of the disease, I call it aetiological therapy,
which comes to approximately the same thing as the therapeutic
endeavours which are referred to in other quarters as causal,
radical, abortive, etc.

Now I must speak on a special subject in
which serum therapy takes its place with those methods of
combating infectious diseases such as Jenner's smallpox
vaccination, Pasteur's anthrax prevention, Pasteur's hydrophobia
treatment, and Koch's tuberculin
therapy.

These kinds of treatment can be indicated
as isotherapeutic methods because they treat the infectious
diseases with media which are of the same kind as the
disease-causing, infective substances. Briefly expressed, serum
therapy works through anti-bodies, iso-therapy through
iso-bodies.

You know that by treating horses with an
iso-body, the diphtheria poison, we obtain the curative
anti-body. In explaining the nature of isotherapy, I would like,
however, to start with an example where, for me, the isotherapy
is not just a means to an end, but an end in itself. This is the
case in the experiments which I have been carrying out for a
number of years in Marburg with the purpose of combating
tuberculosis in cattle.

As you know, tuberculosis in cattle is one
of the most damaging infectious diseases to affect agriculture.
It causes premature death in affected animals, damages nutrition
and milk production and is the cause of inferior meat.
Furthermore, it is feared as being a carrier of tuberculosis to
humans, although admittedly R. Koch recently disputed this.

In different countries, or in different
regions of the same country, the disease does not always strike
with the same violence and frequency. Thanks to the support of
Count Zedlitz, the Lord-Lieutenant of Hesse-Nassau, I have been
in a position to ascertain some remarkable statistical facts in
this connection. As a result of many thousands of tuberculin
inoculations in two areas of the province of Hesse, I at first
thought that the question of breed played an important part. It
appeared, namely, that in the heavy, high milk-yielding strains
(Dutch, Friesian and Swiss cattle) 30 to 40% showed a tuberculin
reaction, whereas in an exceptionally pure breed of red cattle,
raised in Hesse, the so-called Vogelsberger cattle, there was
less than 1%. However, comparative infection experiments carried
out ad hoc in Marburg showed no differences in susceptibility,
and extensive research led finally to the explanation that the
number of cattle reacting to tuberculin is, in the main,
dependent upon whether any or few cattle are kept permanently in
the same stalls. It appeared that, quite independent of hygienic
feeding and living conditions, in almost every case the
cow-houses with 20 and more cattle were heavily vitiated, whereas
the small-man's cows kept in small stables only very occasionally
reacted to tuberculin. The large cow-houses were nearly all
occupied by heavy, high milk-yielding strains and the small ones
by red cattle. And when, in the neighbouring area of
Giessen-Gutshofen, the Vogelsberger cattle, which were in large
numbers kept together in one building, were submitted to
tuberculin tests the proportion of animals which reacted was also
very high.

When making these observations, attention
was also paid to whether, in those areas which had been pointed
out to us by the authorities as being suspected breeding grounds
for human tuberculosis, an especially large number of cases of
bovine tuberculosis was present. But such a coincidence was
definitely not found to exist.

One could feel inclined to use this
observation (which I passed on to the Lord-Lieutenant at the
beginning of this year in an official report) as corroborative
evidence for the view expressed by R. Koch that the tubercle
bacilli are different in humans and in cattle. My own
observations, however, point more to the view that spontaneously
occurring cases of cattle tuberculosis are no more caused by
passing contact than is the case with humans, but that rather
cohabitation of long duration is required if infection leading to
tuberculosis is to be passed from individual to individual.

In my experience cattle are on a relatively
low susceptibility plane with regard to tuberculosis infection.
In a series of cases, I introduced tuberculosis virus, from pearl
nodules containing tubercle bacillus, under the skin direct from
animal to animal, achieving in this way nothing more than a local
tuberculosis with extensive proliferation of bacilli, which after
existing for months completely disappeared. After intravenous
injection of the emulsified pearl nodules I observed a general
feverish condition lasting for weeks, but which also cleared up
spontaneously. Many of these spontaneously cured cattle I later
infected together with fresh control cattle in such a way that
the latter died of acute miliary tuberculosis in 4-6 weeks,
whereas those which had recovered earlier were quite healthy
again after a short indisposition.

If there is to be any certainty of cattle
dying after a single, arbitrary infection with tuberculosis
virus, it is essential that consideration be given to the
following main factors:
(1) origin and special composition of the virus;
(2) method of application;
(3) dosage.

I can confirm absolutely Koch's statement
that many tubercle-bacilli cultures of human origin are no more
dangerous to cattle than Arloing's homogeneous bacilli culture is
to guinea-pigs.

In my own experiments with tubercle bacilli
of human origin which were avirulent to cattle, cultures were
always used which had been cultivated for years in the
laboratory. If, however, I used human cultures for cattle
infection which had only recently been cultivated from tubercular
sputum, they proved by no means unharmful. In the same way, those
human bacilli which had become avirulent to cattle through
long-continued culture in the laboratory can act again with
considerable virulence in cattle if they are first used to infect
goats and then, after the death of the animals, are cultivated
from the carcases. I have a strain of human-goat tubercle bacilli
which, after culture, is probably the most virulent of all to
cattle.

There is more probability that
cattle-virulent cultures can be obtained without first being
passed through goats if the culture stock is obtained from the
body of the cattle. Even here, however, I have gained the
impression that a long period of cultivation on artificial
nutrient medium curtails the disease-causing activity in
cattle.

It is very noteworthy here that one must
certainly not conclude that the loss of disease-causing activity
for cattle necessarily means a decrease in virulence for other
animals. The Pasteur Anthrax studies establish, in fact,
that there is a definite scale for the decline in virulence. A
weakened anthrax strain no longer fatal to mice is not fatal to
any other kind of animal either, and one which is virulent for
rabbits proves always extra virulent for guinea-pigs and mice. It
would be very surprising indeed and would strain credulity if
anyone were to report an anthrax strain which is virulent for
rabbits, but not for mice and guinea-pigs. There is a firm scale
here in accordance with which all anthrax strains, wherever and
however they may be obtained, act with greater disease-causing
energy in mice than in guinea-pigs, and with greater energy in
guinea-pigs than in rabbits.

In the case of tuberculosis things are
different. I have studied with special care in this direction
three tubercle bacilli modifications: tubercle bacilli from human
beings (Tb-Hu), tubercle bacilli from cattle (Tb-Ca) and tubercle
bacilli weakened according to Arloing (Tb-Arl). Tb-Hu and Tb-Ca
remain, with great obstinacy, virulent to guinea-pigs and
rabbits, but behave differently, in so far as Tb-Hu loses its
Ca-virulence more quickly than Tb-Ca. Tb-Arl are harmless to
human beings; in rabbits and horses, when injected intravenously,
they cause severe illness which can quite soon end in death with
symptoms of pneumonia.

For my tuberculosis strains, therefore, I
have a quite different virulence scale, according to the kind of
animal which is being taken as standard. The reaction of horses
is quite exceptionally striking. In these animals the tubercle
bacilli obtained from cattle show the lowest degree of
virulence.

As regards my methods, I test the
disease-causing energy in cattle in three ways: through infection
from the subcutaneous tissue, through intravenous injection of
the emulsified tuberculosis virus, and through intra-ocular
infection. With my assistant, Dr. Römer, I have found that
intra-ocular infection is the most effective. I was led to this
method of infection by a study of the work of Professor
Baumgarten of Tübingen and I now use the intra-ocular
infection method to determine the degree of artificially achieved
tuberculosis immunity in my cattle. Next I use intravenous
infection and lastly subcutaneous infection.

Even when using the tubercle bacilli most
virulent to cattle, the culture dose must not be too small
in the case of intravenous infection if it is required to cause
an illness severe enough to lead to the death of the animal. As
an average dose for this purpose, I take 0.04 g from a culture
not more than 6 weeks old. The quantity of bacilli contained in
this dose corresponds approximately to 2 cm3 of
tuberculosis bouillon culture. With intra-ocular infection, a
much stronger action is achieved with a much smaller quantity of
bacilli. Here the propagation rate in the eye itself is very
considerable.

After observing several cases of
spontaneous recovery in tuberculosis-infected cattle, the thought
occurred to me that the tubercle-bacilli modifications which were
only slightly active in the case of cattle behaved in the same
way as the vaccines to the destructive virus. I then undertook an
experiment aimed at systematically rendering young cattle
immune to tuberculosis with living tubercle bacilli. An exact
description of these immunization experiments, with detailed
records and temperature curves, will most probably follow in
March of next year in my "Beitrage zur experimentellen Therapie".
At this point, I should like to emphasize the following results:
in the case of cattle, I forego the subcutaneous preliminary
treatment and use instead exclusively the intravenous injection.
As immunization vaccine I use a little Ca-virulent Tb-Hu (3267),
then go over to Tb-Ca (Nocard) and, finally, I use nothing
stronger in the way of tuberculosis virus than a goat-passage
culture.

I have also made experiments using an
originally strong tuberculosis virus which has then been dried
under vacuum conditions at room temperature and left standing for
a long time, whereby its disease-causing potential is greatly
reduced. Where pure cultures on artificial nutrient media were
concerned, I was not very satisfied with the results; the
experiments with dried pearl nodules and tubercular organs from
cattle turned out better.

If, on account of the preliminary
treatment, a cow became immune to Ca-virulent Tb-(cultures), then
there was also an immunity against Ca-virulent Tb-Hu
(goat-passage) and vice versa. This does not appear to confirm
that Tb-Hu and Tb-Ca are different in kind.

After my Marburg experiments showed the
possibility of tuberculosis immunization for cattle, we
were now faced with the task of finding out, by research through
special experiments, in how short a time and with what minimum of
detriment to the animal to be immunized and financial sacrifice,
tuberculosis protection for cattle could be achieved in practice.
In order to carry out these investigations, I procured for myself
living space and grazing ground for a large number of cattle and
I am hoping to use the large money award which has come to me
through the Nobel Foundation to show the possibility and
practicability of fighting tuberculosis in cattle along the lines
of Pasteur's protective inoculation to a larger extent than up to
now. It would give me much honour and pleasure if any among you
would care to inspect my Marburg work and installations on the
spot and see, at the same time, how I am using my best
endeavours, in accordance with the intention of the noble founder
himself, Alfred Nobel, to promote the common good.

I need hardly add that the fight against
cattle tuberculosis only marks a stage on the road which leads
finally to the effective protection of human beings against the
disease. Here, however, it has been my intention to report on
facts, not hopes. And it is as a fact that I think I am able to
report the immunization of cattle against tuberculosis to
you.

*As far as I can
ascertain, the expression "poison destruction" appears for the
first time in the Abrin study by Ehrlich in the year 1891
(Deut. Med. Wochschr. 1891).